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6 recordsLinked to original sources
PubMed2026

Whole exome sequencing of paediatric patients with Cogan's syndrome to identify monogenic mimics.

OBJECTIVES: Cogan's syndrome (CS) is a rare variable vessel vasculitis, describing sensorineural hearing loss (SNHL), inflammatory ocular disease and vestibular dysfunction. We hypothesized that within paediatric-onset (p)CS, a proportion would have monogenic disease, either autoinflammatory and/or associated with SNHL. METHODS: Whole exome sequencing (WES) was performed and analysed using an in-house pipeline incorporating virtual gene panels for inflammation and SNHL; copy number variant analysis (ExomeDepth); and phenotype-driven variant prioritization (Exomiser). Genetic variants were interpreted by a multi-disciplinary team according to American College of Medical Genetics and Genomics guidelines. RESULTS: Ten patients with a clinical diagnosis of pCS were enrolled. Three/10 (30%) had a monogenic contribution to the phenotype based on Class 4/5 variants: de novo NLRP3 p.T915R (n = 1) associated with Cryopyrin-associated periodic syndrome; MYO7A p.K542Qfs*5 (n = 1) causing SNHL; and HBB homozygous p.E7V causing sickle cell disease (associated with hearing loss and uveitis). A further two cases had possible monogenic contribution with the following rare variants of uncertain significance (class 3): ADGRV1 compound heterozygous variants (n = 1) associated with Usher syndrome; and a novel ALPK1 p.H735P (n = 1), associated with Retinal dystrophy Optic nerve oedema Splenomegaly Anhidrosis Headache (ROSAH) syndrome. CONCLUSIONS: In children presenting with features suggesting CS, genetic screening should be considered before conferring this rare diagnostic label since at least 30% had an alternative monogenic contribution to the phenotype rather than true pCS, with implications for treatment and prognosis. We thus advocate for genetic testing using next-generation sequencing for patients presenting with pCS.

Humans↗
PubMed2026

Selective saccular plasticity under microgravity links peripheral transcriptomic remodeling to postflight vestibular dysfunction.

Long-duration exposure to microgravity disrupts human balance and spatial orientation, yet the molecular mechanisms underlying vestibular adaptation to spaceflight remain poorly understood. Here, we tested the hypothesis that the saccule, the primary gravity-sensing otolith organ, undergoes selective remodeling during spaceflight and contributes to transient postflight postural instability. Using a cross-species approach, we combined transcriptomic analysis of mouse otolith organs with physiological assessments in astronauts. Laser microdissection-based RNA sequencing of mouse otolith sensory epithelia after a 35-d spaceflight revealed pronounced, organ-specific transcriptomic remodeling in the saccule, whereas the utricle remained stable. Principal component and clustering analyses demonstrated that the saccular transcriptome shifted toward an utricle-like profile under microgravity, accompanied by changes in genes related to synaptic and neuronal function. Promoter motif analysis identified NFAT-associated transcriptional networks, suggesting Ca2+-dependent regulation of synaptic plasticity as a potential molecular substrate of gravity-dependent adaptation. In parallel, vestibular testing in astronauts following long-duration missions (157 to 328 d) revealed selective attenuation of saccule-mediated cervical vestibular-evoked myogenic potentials and increased postural sway immediately after return to Earth, while utricle-mediated responses and semicircular canal function were preserved. Both saccular function and postural stability recovered within approximately 10 d. Notably, early postflight postural instability was partially mitigated by noisy galvanic vestibular stimulation, consistent with stochastic resonance-mediated sensory enhancement. Together, these findings identify the saccule as a plastic gravity sensor and establish a mechanistic link between peripheral molecular remodeling and functional balance deficits after spaceflight, providing a framework for developing countermeasures to facilitate vestibular readaptation during human space exploration.

Animals↗
PubMed2026

The social behavioral phenotype of Kabuki syndrome.

OBJECTIVE: This study describes the social-communication and behavioral profile associated with Kabuki syndrome (KS), including exploratory comparisons between individuals with a pathogenic variant in KMT2D (KS1) versus KDM6A (KS2). METHOD: Thirty-five caregivers of children/adults with KS (25F, Mage = 13.45, SD = 7.60) completed the Social Responsiveness Scale 2nd Edition (SRS-2), Colorado Learning Difficulties Questionnaire, and/or Strengths and Difficulties Questionnaire. Descriptive analyses and non-parametric tests were conducted to examine behavioral trends in the entire cohort and to explore differences in social behaviors and autism characteristics between those with KS1 versus KS2. RESULTS: About a third of the sample have a prior diagnosis of autism spectrum disorder, with rates more elevated in KS2 versus KS1 (67% vs. 23%). In the full cohort, 72% fell in borderline/clinical ranges for Peer Problems, while only 3% yielded atypical scores for Prosocial Behaviors. Those with KS1 were rated to show most challenges in restricted/repetitive behaviors (RRBs), which fell in the moderately severe range, compared to other social domains (social communication, social awareness, social motivation). In contrast, social motivation was the sole area rated within normal limits. CONCLUSION: Those with KS2 showed greater difficulties across all social behavior/cognitive domains than KS1 counterparts, albeit both presented with similar severity in RRB and prosocial behaviors. Prominent features of the KS social behavioral phenotype include pronounced difficulties with inflexible behaviors and restricted interests juxtaposed with strong prosocial tendencies. KS2 may confer increased risk for autism-related characteristics, underscoring the need for more systematic investigations.

Humans↗
PubMed2025

History and clinical epidemiology of NF2-related schwannomatosis.

NF2-related schwanomatosis (NF2-SWN) (previously Neurofibromatosis 2) as characterised by bilateral vestibular schwannomas (VS) was first described in 1822. However, due to the erroneous conflation of individuals with bilateral eighth nerve tumours with von Recklinghausen disease (currently Neurofibromatosis 1, NF1) in 1917 the literature was confusing for much of the 20th century. Even when the conditions were separated officially in 1987 (with separate localisation of the genes), NF2-SWN remained classified as a neurofibromatosis despite the tumours pathognomonic for NF1, neurofibromas, not being a feature of NF2-schwannomatosis. It is only in 2022 that NF2-SWN was correctly delineated as a schwannomatosis. The epidemiology of NF2-SWN has only been possible to delineate after the separation of NF2-SWN from the much more frequent nerve sheath predisposing tumour condition NF1. Two research groups have published on the birth prevalence and population prevalence of NF2-SWN in the UK and Finland. The most highly ascertained assessment of NF2-SWN cases from the Manchester region of England (population 4.8 million) gave a diagnostic prevalence of 1 in 50,500 and calculated birth prevalences of 1 in 27,956 respectively. However, an updated prevalence across England in 2024 (population 55 million) gave a prevalence of at least 1 in 58,000. NF2-SWN usually presents with bilateral vestibular schwannoma, but can present with meningioma or spinal tumour or ophthalmic features before a VS diagnosis or with a unilateral VS and other tumours and rarely with a unilateral VS alone. Molecular testing is now extremely helpful in confirming the diagnosis of mosaic (present in up to 50% of de novo cases) versus germline NF2 and distinguishing from other tumour predisposition conditions especially in childhood or cases with less common presentation. This chapter summarises the clinical epidemiology of NF2-SWN differentiating the condition from the overlapping non NF2-SWN.

Humans↗
PubMed2025

Novel genetic determinants contribute to hearing loss in a central European cohort with enlarged vestibular aqueduct.

BACKGROUND: The enlarged vestibular aqueduct (EVA) is the most commonly detected inner ear malformation. Biallelic pathogenic variants in the SLC26A4 gene, coding for the anion exchanger pendrin, are frequently involved in determining Pendred syndrome and nonsyndromic autosomal recessive hearing loss DFNB4 in EVA patients. In Caucasian cohorts, the genetic determinants of EVA remain unknown in approximately 50% of cases. We have recruited a cohort of 32 Austrian patients with hearing loss and EVA to define the prevalence and type of pathogenic sequence alterations in SLC26A4 and discover novel EVA-associated genes. METHODS: Sanger sequencing, single nucleotide polymorphism (SNP) assays, copy number variation (CNV) testing, and Exome Sequencing (ES) were employed for gene analysis. Cell-based functional and molecular assays were used to discriminate between gene variants with and without impact on protein function. RESULTS: SLC26A4 biallelic variants were detected in 5/32 patients (16%) and monoallelic variants in 5/32 patients (16%). The pathogenicity of the uncharacterized SLC26A4 protein variants was assigned or excluded based on their ion transport function and cellular abundance. The monoallelic or biallelic Caucasian EVA haplotype was detected in 7/32 (22%) patients, but its pathogenicity could not be confirmed. X-linked pathogenic variants in POU3F4 (2/32, 6%) and biallelic pathogenic variants in GJB2 (2/32, 6%) were also found. No CNV of SLC26A4 and STRC genes was detected. ES of eleven undiagnosed patients with bilateral EVA detected rare sequence variants in six EVA-unrelated genes (monoallelic variants in SCD5, REST, EDNRB, TJP2, TMC1, and two variants in CDH23) in five patients (5/11, 45%). Cell-based assays showed that the TJP2 variant leads to a mislocalized protein product forming dimers with the wild-type, supporting autosomal dominant pathogenicity. The genetic causes of hearing loss and EVA remained unidentified in (14/32) 44% of patients. CONCLUSIONS: The present investigation confirms the role of SLC26A4 in determining hearing loss with EVA, identifies novel genes in this pathophysiological context, highlights the importance of functional testing to exclude or assign pathogenicity of a given gene variant, proposes a possible diagnostic workflow, suggests a novel pathomechanism of disease for TJP2, and highlights voids of knowledge that deserve further investigation.

Humans↗
PubMed2026

Downbeat nystagmus without ataxia as an early manifestation of spinocerebellar ataxia, autosomal recessive type 10 (SCAR10): a case report.

The differential diagnosis of dizziness is broad and can include both vestibular and autonomic pathology. Vestibular dizziness is typically described as a sensation of movement (e.g. the world is spinning) while dizziness related to autonomic dysfunction is typically described as symptoms of orthostatic intolerance (e.g. postural lightheadedness). It is important to differentiate the type of dizziness to guide proper diagnostic and therapeutic workup. We describe the case of a young patient evaluated in the autonomic clinic for dizziness, ultimately found to have a rare cerebellar neurodegenerative disorder. A 23-year-old female with a past medical history of migraine without aura presented in autonomic clinic with a four-month history of slow, progressive onset of vestibular dizziness. Neurological exam was notable for downbeat nystagmus, but no appendicular or truncal ataxia was appreciated. Subsequent vestibular evaluation was consistent with central vestibular dysfunction. Magnetic resonance imaging (MRI) of the brain with and without contrast was notable for severe cerebellar atrophy. The patient subsequently underwent genetic testing which demonstrated a pathogenic and likely pathogenic variant in the Anoctamin 10 (ANO10) gene, which is seen in Autosomal Recessive Spinocerebellar Ataxia, Autosomal Recessive Type 10 (SCAR10). To our knowledge, this case represents the first reported instance of SCAR10 presenting with the sole neurologic exam finding of downbeat nystagmus without cerebellar ataxia. Additionally, the finding of severe cerebellar atrophy seen on MRI, without gait or limb ataxia on exam is an interesting clinicoradiological dissociation. This case suggests that nystagmus may represent an early disease marker, even in the absence of clinical ataxia in patients with SCAR10.

Humans↗